This proposal will explore genetic variation as a cause of elevated C-reactive protein (CRP) levels that are associated with atherosclerotic cardiovascular disease The CRP locus, including upstream and downstream regulatory regions, will be re-sequenced among cohorts of women with very low (48) and very high (48) CRP levels. Similar re-sequencing will be performed for genes that regulate CRP expression, such as IL6, ILl, CEBPB, CEBPD, STAT3, TGBFB, and TNF. All genetic variation identified will be analyzed for linkage disequilibrium and effect on coding sequence, splicing, and promoter/enhancer elements. All SNPs that are likely to affect gene expression and protein structure, as well as those seen at >10% frequency will be analyzed to identify haplotype-tagging single nucleotide polymorphisms (htSNPs). Larger cohorts of 800 women, each with very low and very high CRP, will be genotyped at multiple loci to assess association between alleles of these genes and baseline CRP levels. Depending on results, further analysis of these SNPs, or SNPs from additional genes, will be studied in this population. Ultimately, we hope to identify molecular markers associated with high or low CRP, and thus with atherosclerosis risk.